Oncology & Cancer Research

Abemaciclib is a well-known CDK4/6 inhibitor. Although it is known to be an effective treatment for breast cancer, its action against other forms of cancer has not been determined. Canine malignant melanoma is a common cancer in dogs and is quite aggressive. It is thought that targeting the same CDK4/6 pathway may be effective in this type of cancer too.

In Vitro Testing

Recently, a research team at Seoul National University tested this possibility. They tested five canine malignant melanoma cell lines with a wound healing assay and vacuolization inhibition determination. The cells were treated with various levels of abemaciclib or a combination of abemaciclib and fenbendazole together. Of these five cell lines, the one with highest sensitivity and synergistic response to the treatments was selected for further in vivo study.

In Vivo Testing

For the in vivo study, a mouse model was first inoculated with the most responsive cell line, UCDK9M5, and the tumor allowed to develop to a standard size. Then, the treatment was administered by oral gavage once a day for 13 days. The tumor size was measured throughout the duration of the experiment.

Results

The results showed that this type of treatment was both effective and well-tolerated. The combined treatment possibly showed a synergistic effect. Further research will be needed to confirm it. These chemicals are both cell cycle inhibitors, but each targets a different phase, so together they have the potential to be more powerful.

Further research on treatment of canine melanoma may benefit both dogs and humans. Malignant melanoma remains fatal in both animals, and canine melanomas hold a unique value as a translational model.

As found by comparative oncology, canine melanomas turn out to be close models for human melanomas. This is particularly useful because several rare human melanoma subtypes have canine counterparts that are frequently observed naturally occurring in dogs. Therefore, developing treatment for a type of cancer in dogs that is rather common may translate well as treatment for what is a rare cancer in humans.

Kim S, Choi J, Suh Y, et al. Abemaciclib induces G1 arrest and lysosomal dysfunction in canine melanoma cells: synergistic effects with fenbendazole. Front Vet Sci. 2025 Jun 26:12:1603686. PMID: 40642276

Pancreatic ductal adenocarcinoma is a highly malignant form of cancer and the most common form of pancreatic cancer. It most often is only diagnosed at advanced stages, leaving dismal outlooks. Chemotherapy for this cancer has centered around gemcitabine for several decades. Unfortunately, the cancer is quick to develop resistance to gemcitabine and then the drug fails to remain effective.

To improve treatment efficacy, combination therapy is often the next step. However, combination therapies are often even more toxic overall. Because of increased toxicity, another desired improvement is the ability to deliver the chemical directly to the tumor, with less impact on the healthy cells and tissues. Unfortunately, conventional nanocarrier systems tend to result in severe hepatotoxicity and inadequate delivery to the tumor site.

Recently, researchers at Zhejiang University School of Medicine attempted to treat pancreatic cancer by targeted delivery using vesicles containing combination treatment of gemcitabine and RP-6306. Working with a mouse model they found that this method of drug delivery was effective. The drugs were delivered to the tumor microenvironment as intended, while successfully avoiding inducing cytotoxic effects.

While gemcitabine disrupts DNA synthesis, RP-6306 disrupts the G2/M checkpoint by silencing PKMYT1, thereby inducing PANoptosis. This combination effectively targeted the cancer cells without inducing organ damage. The use of vesicles showed superior biocompatibility and minimal toxicity. Further studies of this combination are warranted as the current work shows great promise.

Chen J, Ren J, Zhang C, et al. Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe. Cell Death Dis. 2025 Jul 15;16(1):526. PMID: 40664640

Gastric cancer is one of the leading causes of cancer deaths worldwide. It is known to be an aggressive type of cancer and unfortunately, is often undiagnosed until already reaching an advanced stage. One of the main treatments for gastric cancer is radiation therapy, however, the cancer cells are sometimes quick to develop radioresistance, creating another obstacle to overcome.

New research recently completed at Nantong University investigated a method to treat radioresistant gastric cancer cells. A well-known natural product, β-elemene, stood out as having potential to act as a radiosensitizer. β-Elemene is found in the plant Curcuma zedoaria, which has been used as a spice similar to ginger. Previous studies have suggested that it may act as a radiosensitizer against cancer cells.

For this study, 2 human gastric cancer cell lines, known to have different characteristics and behaviors, were used. These cell lines were radiated and then the surviving cells propagated several times, resulting in radioresistant populations.

Next, the radioresistant cancer cells were subcutaneously injected into a mouse model. The growth of the tumor was monitored until the size was appropriate, approximately 2 weeks. Then the treatment with β-elemene, radiation, or combination was begun. The treatments were administered for 20 days, and then finally the mice were sacrificed, and the tissues analyzed.

The results of this study showed that the combination of β-elemene together with radiation was the most effective option. With either chemical or radiation alone, the tumor growth was slowed, however, the combination treatment was even more effective. It is thought that the β-elemene is responsible for modulating ferroptosis, which strongly impacts some of the tumor-associated proteins.

Further structural and biochemical analysis should be done which will help develop the targeted therapy. Perhaps the reliance of the radioresistant cancer cells on ferroptosis can be successfully exploited so that the cancer cells can be finally destroyed.

He J, Li M, Bao J, et al. β-Elemene promotes ferroptosis and reverses radioresistance in gastric cancer by inhibiting the OTUB1-GPX4 interaction. Front Pharmacol. 2024 Oct 17:15:1469180. PMID: 39484165 

Ginsenosides are the naturally occurring steroid compounds found in ginseng. Approximately 100 different ginsenosides have been identified so far and most of these have some biological activity including anti-tumor effects.

Recently, the effects of ginsenoside Rg1 against the malignant tumors of multiple myeloma were observed. Multiple myeloma is generally treated with bortezomib, however, the emergence of drug resistance against this treatment has increased in recent years. There is need for a new treatment or combination treatment to battle this cancer.

In a new study at Ningbo University, a drug-resistant cell line RMPI8226R was constructed. Next, a four-week-old nude mouse model was subcutaneously inoculated with either the ‘normal’ cancer cells or these drug-resistant cancer cells. All of the mice developed tumors, which were then allowed to grow to a predetermined size. Once the tumors were well-developed, treatments were begun.

The treatments involved intraperitoneal injections of either bortezomib, or ginsenoside Rg1, or a combination of bortezomib + ginsenoside Rg1. Injections were continued every 3 days for 15 days. After that time, the tumors were collected and analyzed.

The results showed that treatment with ginsenoside Rg1 was able to inhibit the development of multiple myeloma tumors. It was also found that the addition of ginsenoside Rg1 to bortezomib treatment was able to overcome the drug resistance. This proved the anti-tumor effect of ginsenoside Rg1, however, only one multiple myeloma cell line RMPI8226 was investigated so far. Further research including additional cell lines is needed.

Ginsenoside Rg1 as well as several other ginsenosides are available from LKT Labs: see all

Lin L, Chen D, Li S, et al. Ginsenoside Rg1 inhibits multiple myeloma and overcomes bortezomib resistance through AMPK-mTOR pathway. Heliyon. 2024 Jul 1;10(13):e33935. PMID: 39071579

Caerulomycin A is a microbial metabolite isolated from marine actinomycetes. The chemical structure consists of a 2,2′-bypyridine core, which is similar to a biphenyl core. Because of this similarity, it is thought that it may bind well to tubulins and DNA topoisomerase, and thereby provide a potent anti-cancer affect.

In vitro and in vivo studies have shown caerulomycin A to be effective against paclitaxel-resistant cancer. In a study at Ohio University, several types of human tumor cell lines were prepared in vitro and treated with caerulomycin A and in combination with paclitaxel. The melanoma cells were also injected subcutaneously into a mouse model for in vivo study. The mice were then administered caerulomycin A by intraperitoneal injections.

The in vitro studies showed the growth of all cancer types was inhibited, including the paclitaxel-resistant cancer cells. The animal model was also effective and confirmed a significant reduction in tumor size.

The results of this study suggest a synergistic effect when used in combination with paclitaxel against several cancer types. Further work with caerulomycin A and related compounds may offer a new strategy for cancer treatment.

Tong L, Sun W, Wu S, et al. Characterization of caerulomycin A as a dual-targeting anticancer agent. Eur J Pharmacol. 2022 May 5:922:174914. PMID: 35337812

Capsaicin has been identified as the primary component that contributes to the hotness of chili peppers. Around the world, chili peppers are a popular ingredient used in many kinds of food. There are many varieties of chili pepper and each offers a slightly different flavor and level of heat. In some communities they are even used as a food staple.

Over time, this ingredient and its possible role in cancer has become a subject of controversy. While some studies with capsaicin have shown that it can inhibit cancer cell growth and metastasis, other studies have shown the opposite result.

Recently, a study at Nanjing University focused specifically on a diet with high level of capsaicin and its impact on gastric cancer. This study used a xenograft mouse model of gastric cancer fed with a diet of either 50 mg/kg or 100 mg/kg capsaicin. This is the equivalent of a human consuming 90-250 mg capsaicin each day. The results showed that this type of diet led to increased metastasis rates and increased number of cancer nodules. Interestingly, the size of the tumors did not increase.

While other experiments have given evidence of capsaicin having anticancer properties, this study gives evidence of its cancer promoting properties. One key difference between studies is likely to be the concentration or intensity of the application. Perhaps at lower concentration and frequency of consumption, there is a beneficial effect, but with continual high concentration intake as in this study, the effects become detrimental. It seems chili peppers provide yet another example of ‘moderation is key’.

Deng R, Yu S, Ruan X, et al. Capsaicin orchestrates metastasis in gastric cancer via modulating expression of TRPV1 channels and driving gut microbiota disorder. Cell Commun Signal. 2023 Dec 21;21(1):364. PMID: 38129926

Gastric cancer has severe morbidity and mortality rates and is the fifth most common cancer globally. This cancer is known to metastasize aggressively, making it very challenging to control. Research has shown histone deacetylase 6 (HDAC6) being related to this specific cancer and has therefore become a target in searching for an effective treatment.

Carbenoxolone disodium has been identified through the use of high-throughput screening as an inhibitor of HDAC6. Carbenoxolone disodium is an active metabolite of glycyrrhizic acid, a natural compound known for its anti-inflammatory properties. A recent study at Zhengzhou University tested the effectiveness of carbenoxolone in cell culture studies and in a mouse model.

In the cell culture studies, normal gastric cells were tested alongside two types of gastric cancer cells. The test results showed that carbenoxolone could block the growth of the cancer cells without showing toxicity to the normal cells. This indicates that this chemical may be a relatively safe agent. The tests also showed that carbenoxolone blocked the wound healing of the cancer cells, inhibiting the migration capacity. And finally, the process of epithelial-mesenchymal transition was reversed after the treatment. Epithelial-mesenchymal transition is an important process allowing cancer cells to increase their mobility.

In the animal study, nude mice and the gastric cancer cells were used to establish a lung cancer metastasis model. Afterwards, oral treatment with carbenoxolone was administered. The results of this experiment showed that carbenoxolone treatment significantly inhibited the lung metastasis.

This study confirms carbenoxolone disodium to be a selective and potent inhibitor for HDAC6 in gastric cancer cells. This is a good lead for development of an anti-metastasis drug against gastric cancer.

Song Z, Zhao C, Yan J, et al. Carbenoxolone disodium suppresses the migration of gastric cancer by targeting HDAC6. Future Med Chem. 2023 Feb;15(4):333-344. doi: 10.4155/fmc-2022-0246. PMID: 36946221

Shikonin is a naturally occurring compound found in Gromwell roots, traditionally used in Chinese medicine for various purposes. Interestingly, shikonin and the related naphthoquinone compounds are responsible for the red/purple color of the roots. Studies have shown that shikonin itself has antibacterial, anti-inflammatory, and anti-tumor effects. Recently, a new study investigated the effects on brain tumors.

The difficulty in treating brain tumors is the presence of the blood-brain barrier and also the blood-tumor barrier. These barriers prevent most small molecules from crossing, and therefore brain tumors are protected from most chemical treatments. Furthermore, the current standard treatment for glioblastoma includes chemotherapy with temozolomide, however, the glioblastoma cells very quickly develop resistance to this chemical.

In vitro studies showed that shikonin does inhibit glioblastoma cells quite effectively. Therfore, an alternative method of delivery was attempted to cross the barriers. First, lab mice were infused with cancer cells directly into the thalamus. Next, direct intracranial infusion of shikonin was applied into the same spot. By this method, the blood-brain and blood-tumor barriers are physically passed through by the injection needle. In this way, the effect of the treatment in a living system can be observed.

For this study, 2 different brain cancer cell lines were used. The mice from either group, when treated with shikonin, showed significantly longer survival times. Some of the mice were treated with combination of shikonin and temozolomide or temozolomide alone. The effects of the combination treatments were inconclusive. Once cancer cell line seemed to have even better success with a combination treatment, but the other line did not. In addition, neither cancer line, when treated with temozolomide alone, showed significant improvement.

Although shikonin has poor bioavailability and cannot cross the blood-brain barrier on its own, most chemical treatments will face the same problem. Therefore, using direct intracranial infusion may help develop more effective treatment for brain tumors.

Maeoka, R, Ouji Y, Nakazawa T, et al. Local administration of shikonin improved the overall survival in orthotopic murine glioblastoma models with temozolomide resistance. Biomed Pharmacother. 2023 Oct:166:115296. PMID: 37557011

Oridonin is a naturally occurring chemical that can be extracted from the Chinese sage bush Isodon rubescens, formerly known as Rabdosia rubescens. It is used in traditional Chinese medicine to block cancer metastasis and recurrence and to overcome therapeutic resistance. Recently, a new study has been completed which looked at its effects on a lung cancer xenograft mouse model.

To begin, the mice were injected subcutaneously with human lung cancer cells. The tumors were allowed to grow and develop to a specified volume prior to beginning treatment. Once the tumors were developed, oridonin was injected intraperitoneally five times each week. In addition, NK-92MI cells were injected intravenously once a week. These “natural killer cells” are a naturally occurring part of an immune system. However, the mouse model used for this experiment does not have a functioning immune system. Therefore, the killer cells were injected during the study.

The results of the study showed that oridonin treatment enhanced the activity of the natural killer cells against all three different cancer cells lines studied. It was also revealed that ordidonin seems to be non-toxic to the liver and kidney. This is exciting because selectively harming only cancer cells without effecting normal cells always proves to be a challenge.

Understanding of the immunostimulatory effect of oridonin on NK cells more thoroughly may help to develop a new lung cancer treatment.

Hwang T, Chang C. Oridonin enhances cytotoxic activity of natural killer cells against lung cancer. Int Immunopharmacol. 2023 Sep;122:110669. doi: 10.1016/j.intimp.2023.110669. PMID: 37480753

Prostate cancer is the second most common cancer worldwide, leading to more than one million diagnoses per year. Metastatic prostate cancer is commonly treated with hormone therapy. These cancer cells need activation of the androgen receptor to divide, so drugs that drop testosterone levels block tumor growth. Unfortunately, resistance to hormone therapy tends to develop in one to two years.

Resistance often involves cancer cells reactivating the androgen receptor without needing testosterone. The authors of a recent study were interested in finding a way to re-inactivate it. The protein CDK7 is an attractive drug target because it is involved in both androgen receptor regulation and cell cycle regulation. The drug CT7001 inhibits CDK7, and shows promising experimental results in several other cancers. Therefore, these authors tested the effectiveness of CT7001 in prostate cancer.

They found that in prostate cancer cell lines, CT7001 binds to CDK7. This molecule also inhibits the androgen receptor, inhibits cell growth, and causes cell cycle arrest. The authors then treated mice carrying prostate cancer tumors with CT7001, or enzalutamide (a drug that blocks testosterone), or both. CT7001 shrank tumors, and the combination of CT7001 and enzalutamide worked even better.

The in vitro and mouse evidence from this study suggests that this chemical could help fight this disease, especially in combination with hormone therapy drugs.

Constantin T, Varela-Carver A, Greenland K, et al. The CDK7 inhibitor CT7001 (samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer. Br J Cancer. 2023 Jun;128(12):2326-2337. PMID: 37076563. doi: 10.1038/s41416-023-02252-8

Cembrenediols are naturally occurring compounds found in fresh tobacco. However, the commercial tobacco products that many people know and love are purposely fermented to produce customized flavors, which degrades the cembrenediol. This is unfortunate, because while it is well-known that tobacco contains several carcinogens, cembrenediol is actually found to have anticancer activities.

A recent study on prostate cancer used a mouse model to demonstrate that treatment with cembrenediol prevented recurrence of this cancer. The mice were first implanted with prostate cancer cells, which were allowed to develop into tumors. The tumors were then removed, followed by 8 weeks of treatment with cembrenediol. At the end of the study the animals were sacrificed and the organs examined. The animals that had received cembrenediol treatment showed much lower chance of cancer recurrence compared to vehicle-treated animals.

Experiments were also run on human prostate cancer cell lines. The cells struggled to grow when treated with the cembrenediol. The treated cells showed lower migration capability and lower colony formation capability. Further evidence suggests that this treatment impacts the metabolism of these cancer cells.

Additionally, the cembrenediols and analogs have been found to be potent inhibitors for other cancers as well. Therefore, although tobacco is generally known for its cancer-causing potential, it may be possible that this plant, when processed and used another way, may provide effective cancer treatment.

Cembrenediols available at LKT Labs:

α-Cembrenediol

β-Cembrenediol

β-Cembrenediol Methyl Ether

Mudhish E, Siddique A, Ebrahim H, et al. The tobacco β-Cembrenediol: a prostate cancer recurrence suppressor lead and prospective scaffold via modulation of indoleamine 2,3-dioxygenase and tryptophan dioxygenase. Nutrients. 2022 Apr 4;14(7):1505. doi: 10.3390/nu14071505. PMID: 35406118

Merkel cell carcinoma is a rare and aggressive skin cancer. As it begins, a painless red or blue lump in the skin forms, and then metastasizes quickly. After metastasis, patients have a terrible prognosis, with only an 18% survival rate after five years. Moreover, the incidence of this malignant carcinoma is increasing.

Currently, few therapies are available for metastatic Merkel cell carcinoma. Fortunately, immunotherapies have recently been approved as treatment, but unfortunately, most patients eventually develop resistance.

Enzyme Inhibition Tactic

Because this cancer is so difficult to treat, a team of cancer researchers in California became interested in targeting Aurora kinase A to attempt to treat this cancer. Aurora kinase A is an enzyme needed for cell proliferation, and is overexpressed in many types of cancer. In theory, by inhibiting this enzyme, the growth of the cancer will be repressed. For this reason, an inhibitor specific to Aurora kinase A , LY3295668, has recently been developed. Therefore, the researchers decided to test the effectiveness of LY3295668 against Merkel cell carcinoma in cell culture.

Cell and Animal Testing

The first test involved the application of LY3295668 to Merkel cell carcinoma cell lines. The result was that Ly3295668 inhibited the cell growth and raised levels of biomarkers of cell cycle arrest and apoptosis. Then to investigate further, mice bearing Merkel cell carcinoma tumors were created. In these mice, after treatment with LY3295668, the tumors shrank. However, when the researchers stopped LY3295668 treatment, the tumors grew again and were resistant to further LY3295668 treatment.

Insufficient Results

These results suggest that LY3295668 has the potential to treat this type of carcinoma, but that this cancer can develop resistance to this drug quickly. As noted, this chemical does show effectiveness against the cancer, however, the overall result is rather insufficient. In consequence, if LY3295668 is to be developed into a clinical treatment, it will in all likelihood need to be used in combination with other drugs.

Das B, Kannan A, Nguyen Q, et al. Selective inhibition of aurora kinase A by AK-01/LY3295668 attenuates MCC tumor growth by inducing MCC cell cycle arrest and apoptosis. Cancers (Basel). 2021 Aug;13(15):3708. doi:10.3390/cancers13153708. PMID: 34359608.

Background

Sotorasib and adagrasib are two new compounds that can help us to understand the mechanisms of KRAS mutations. Mutated forms of the gene KRAS encourage cell proliferation and are involved in a large fraction of all cancers. Although this gene was discovered in the 1980s, scientists have long struggled to find chemotherapies that target it. That’s because of a lack of binding sites. The new drugs sotorasib and adagrasib can bind to and inhibit one kind of mutated KRAS. Sotorasib has been approved for the treatment of non-small-cell lung cancer and adagrasib is in clinical trials.

Non-small-cell lung cancer has a history of developing resistance to drug treatments. So, it’s likely that patients may suffer resistance when sotorasib and adagrasib enter clinical use. Recently, a team of cancer researchers sought to understand resistance to these new drugs, to improve strategies to prevent it.

Experimental

The researchers exposed a cell culture line of non-small-cell lung cancer to sotorasib or adagrasib, with added N-ethyl-N-nitrosurea to encourage mutations. Then they analyzed the KRAS mutations that resulted. Five of the mutations were resistant to one drug but not the other. Therefore, sequential treatment with these drugs might help patients with this kind of resistance. Two of the KRAS mutations that emerged were resistant to both drugs. A cocktail of BI-3406 and trametinib inhibits cells with this mutation, so this cocktail might help patients who have this kind of resistance.

The mutations found in this study are not exhaustive of all the KRAS mutations. Additional mutations may appear when patients are treated with these chemicals. However, this study made good progress toward understanding the mechanisms behind KRAS chemotherapy resistance.

Koga T, Suda K, Fujino T, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. Journal of Thoracic Oncology. 2021 Aug;16(8):1321-1332. PMID: 33971321. doi: 10.1016/j.jtho.2021.04.015

Ovarian cancer often grows undetected into the advanced disease stages and because of this the mortality rate is relatively high. Even after using the available treatments, relapse is quite common. Recent studies of several cancers have shown positive impacts when treated with HDAC inhibitors, and even more powerful impacts when treated with an HDAC inhibitor paired with other types of inhibitors.

Cell Study

A recent study on ovarian cancer cells paired HDAC inhibitor panobinostat (LBH-589) with autophagy inhibitor chloroquine or bafilomycin A1. Together they cause DNA strand breaks and inhibit the cell’s ability to repair those breaks. The combination treatment was more powerful than the individual treatments. Discovering synergistic drug combinations such as these is the cornerstone of cancer therapy.

Animal Study

In another study, panobinostat was paired with PARP inhibitor olaparib. Mice with epithelial ovarian cancer cells were divided into 4 groups and each group subjected to one set of treatment: vehicle, panobinostat, olaparib, or panobinostat + olaparib. It was discovered that PARP inhibitors and HDAC inhibitors synergize well against HR-proficient ovarian cancer. This is exciting because HR-proficient type has proven less responsive to the developed treatments than HR-deficient type, which is more common. The overall tumor burden in the mice treated with panobinostat + olaparib was reduced. Also, there was reduced tumor proliferation and increased DNA damage observed in the harvested tumors.

Using the dual mechanisms of an HDAC inhibitor combined with another type of inhibitor is found to have a synergistic effect in many instances. The rational combination of drugs to target both cytotoxic effects and immune-modulating effects at the same time increases the potential to overcome drug resistance. This is especially important in fighting cancers such as ovarian cancer that have high mortality rates.

Ovejero-Sanchez M, Gonzalez-Sarmiento R, Herrero AB. Synergistic effect of chloroquine and panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair. Neoplasia. 2021 May;23(5):515-528. doi: 10.1016/j.neo.2021.04.003. PMID: 33930758

Wilson A, Gupta V, Liu Q, et al. Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer. Neoplasia. 2022 Feb;24(2):63-75. doi: 10.1016/j.neo.2021.12.002. PMID: 34933276

Astaxanthin is a natural pigment that makes many sea creatures red, such as shrimp and crabs. It has many commercial uses such as a food coloring and an animal feed supplement, and it is an antioxidant. Previous research has found that astaxanthin has an antitumor effect.

Glioblastoma is a type of brain cancer with an especially poor prognosis. It is difficult to treat because most cancer drugs can’t cross the blood-brain barrier to reach the brain tumor. Some natural products such as curcumin can cross the blood-brain barrier. Recently, a team of scientists in Japan set out to test whether astaxanthin can cross the blood-brain barrier and whether it can act against glioblastoma tumors.

First, the researchers added astaxanthin to a cell culture line of mouse glioblastoma cells. They found that the cells had reduced proliferation and migration, both of which are needed for tumors to spread.

Then they fed astaxanthin to mice and were able to detect it in mouse brains, suggesting that astaxnthin can cross the blood-brain barrier. The researchers fed astaxanthin to mice with a model of glioblastoma and the tumor growth was notably inhibited.

Astaxanthin may inhibit glioblastoma growth because it is an antioxidant. Antioxidants can affect the cell signals that control growth and division. The antitumor effect of astaxanthin in this experiment was modest, but astaxanthin is worth researching in combination with other promising glioblastoma drugs.

Tsuji S, Nakamura S, Maoka T, et al. Antitumor effects of astaxanthin and adonixanthin on glioblastoma. Marine Drugs. 2020 Sep 18;18(9):474. doi:10.3390/md18090474. PMID: 32962073.

Most cancer cells get their energy through glycolysis instead of oxidative phosphorylation, even in the presence of oxygen. This process is named the Warburg effect after its discoverer, and it allows cells to proliferate even with damaged mitochondria. In 2008, researchers at Harvard Medical School discovered that one form of pyruvate kinase, PKM2, is required for the Warburg effect. The other form of pyruvate kinase is not involved. These findings make PKM2 an interesting target for developing cancer therapies.

The P13K/Akt/mTOR regulatory pathway is upstream of PKM2. The small molecule LY294002 targets P13K, so recently Lu et al. tested its effect on cancer cell proliferation.

Lu et al. grew several lines of gastric cancer cells in culture. A Western blot analysis found that PKM2 expression was increased in cancer cell lines compared to the control. They chose one cell line to study in detail. LY294002 decreased cell proliferation and increased apoptosis in this line. LY294002 also decreased the activity of lactate dehydrogenase, a biomarker of the Warburg effect.

They wanted to test whether PKM2 was part of the mechanism by which LY294002 decreased cell proliferation, so they used siRNA to knock down PKM2 on its own. siRNA-treated cells behaved similarly to LY294002-treated cells: they had lowered proliferation, increased apoptosis, and lowered lactate dehydrogenase activity. Lu et al. concluded that PKM2 is important to the mechanism of LY294002’s action.

LY294002 shows promise as an inhibitor of PKM2 and the Warburg effect.

L4796 LY-294002

L960002 LY-294002 Hydrochloride

Lu J, Chen M, Gao S, Yuan J, Zhu Z, Zou X. LY294002 inhibits the Warburg effect in gastric cancer cells by downregulating pyruvate kinase M2. 2018. Oncology letters. 15:4358-4364.

MELK (maternal embryonic leucine zipper kinase) signals cell division and may play a role in several kinds of cancer. In 2012, researchers screened for inhibitors of MELK and found a substance that they named OTSSP167. OTSSP167 shows promise as a chemotherapy drug.

Bone disease is a top cause of morbidity for multiple myeloma patients. Bone lesions cause bone pain, bone breakdown, and encourage further tumor growth. Even when chemotheraphy causes tumor remission, the bone lesions don’t heal. Bisphosphonates, the current standard of care, come with serious side effects.

Researchers Muller and Bolomsky investigated OTSSP167’s potential to treat multiple myeloma. In 2018, Bolomsky et al. found that OTSSP167 reduced tumor load in a multiple myeloma mouse model. As predicted, it worked by inhibiting MELK. The researchers also found that OTSSP167 reduced multiple myeloma bone disease, even at doses that were too low to inhibit tumor growth. They followed up on their findings in another 2018 paper.

In the follow-up, Muller et al. dosed bone cell cultures and multiple myeloma mice with OTSSP167. They found that OTSSP167 inhibits the growth and function of osteoclasts, cells that reabsorb bone, and stimulates osteoblasts, cells that produce bone. The mice dosed with OTSSP167 had fewer bone lesions and better bone volume than controls.

Muller et al. conclude that OTSSP167 has the potential to treat multiple myeloma tumors and to reduce bone lesions.

O783743 OTSSP167 Hydrochloride

Chung S, Suzuki H, Miyamoto T, et al. Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget. 2012 3(12):1629–1640. doi:10.18632/oncotarget.790

Muller J, Bolomsky A, Dubois S, Duray E, Stangelberger K, Plougonven E, Lejeune M, Léonard A, Marty C, Hempel U, Baron F, Beguin Y, Cohen-Solal M, Ludwig H, Heusschen R, Caers J. Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity in multiple myeloma bone disease. Haematologica. 2018 Vol 103(8):1359-1368.

Bolomsky A, Heusschen R, Schlangen K, et al. Maternal embryonic leucine zipper kinase is a novel target for proliferation- associated high-risk myeloma. Haematologica. 2018 103(2):325-335.

Palmatine is an isoquinoline alkaloid naturally found in plant species such as Corydalis and Phellodendron. It exhibits a wide array of biological effects, such as sedative, antidepressant, antioxidative, anticancer, and antacid activities. In a recent study by Chakravarthy, et al. at the University of Texas Health Science Center in San Antonio, Palmatine has shown potential as an agent for the clinical management of pancreatic cancer.

Advanced pancreatic ductal adenocarcinoma (PDAC) has a notoriously high mortality rate. Current therapies, primarily centered around gemcitabine treatment in combination with other agents, have shown modest success but are limited to select groups of patients.

Pancreatic stellate cells (PSCs) are considered to be the driver of pancreatic fibrosis and are activated by a number of factors, including inflammation. Once activated, PSCs are responsible for the expression of alpha smooth muscle actin and collagen 1 type 1 alpha 1 (COL1A1). Pancreatic cancer cells (PCCs) also activate PSCs. Inhibiting the growth of activated PSCs and PCCs with novel compounds has become one possible strategy for combating PDAC.

Palmatine is one such compound. Chakravarthy, et al. show that palmatine inhibits both the growth of PSCs and inhibits the sonic hedgehog pathway. By disrupting the interaction between PSCs and PCCs, palmatine treatment may be a viable method of clinical management of PDAC, either alone or in conjunction with a chemotherapy agents like gemcitabine.

LKT Labs offers palmatine and other chemotherapy agents like gemcitabine for research use.

P0245 Palmatine

G1745 Gemcitabine Hydrochloride

I6932 Irinotecan

O9201 Oxaliplatin

References:

Chakravarthy D, Munoz A, Su A, et al. Palmatine suppresses gluatmine-mediated interaction between pancreatic cancer and stellate cells through simultaneous inhibition of survivin and COL1A1.  Cancer Lett. 2018 Apr 10;419:103-115. doi: 10.1016/j.canlet.2018.01.057